蛋白化学合成中的片段增溶策略  

Segment Solubilizing Strategy in Protein Chemical Synthesis

作　　者：邓祥宇 张宝昌 曲倩 Xiangyu Deng;Baochang Zhang;Qian Qu(Tsinghua University Tsinghua-Peking Center for Life Sciences,Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology,State Key Laboratory of Chemical Oncogenomics(Shenzhen),Department of Chemistry,Beijing 100084,China;Shanghai Jiao Tong University Institute of Translational Medicine,Shanghai 200240,China)

机构地区：[1]清华大学清华-北大生命科学联合中心生命有机磷化学及化学生物学教育部重点实验室化学肿瘤基因组学国家重点实验室(深圳)化学系,北京100084 [2]上海交通大学转化医学研究院,上海200240

出　　处：《化学进展》2023年第11期1579-1594,共16页Progress in Chemistry

基　　金：国家自然科学基金项目(No.22277073)资助。

摘　　要：蛋白质在多种生物过程和生物医学研究中起到关键作用,获取高度均一性的蛋白质样品是这类生化研究的重要一环。相较于重组表达法,蛋白质化学合成能够更为稳健地获取精准修饰的,甚至是人为设计的蛋白质。而一些可作为药物靶点的重要蛋白(如人源白细胞介素-2、K^(+)通道蛋白Kir5.1等)在化学合成过程中面临多肽片段溶解度不佳的问题,为后续的纯化、表征、连接反应等操作带来困难。这类问题的主要原因可能是这些目标蛋白的多肽片段之间易通过疏水相互作用、氢键等作用模式自组装形成二级结构,进而使得片段溶解度降低。增溶标签策略是这类问题的解决途径之一,本文介绍了在多肽片段主链、侧链和骨架上安装增溶标签的策略,选取膜蛋白FCER1G、共伴侣蛋白GroES等蛋白作为目标展示,并对增溶标签策略未来的发展方向作出展望。Proteins play critical roles in various biological processes and biomedical researches.A significant task of such biochemical studies is to obtain protein samples of high homogeneity with respect to their atomic compositions.Chemical protein synthesis offers a much more robust and effective strategy over recombinant expression technology for accessing proteins that are precisely modified or even artificially designed.However,some important proteins that can be used as drug targets(such as human interleukin-2,K^(+)channel protein Kir5.1,etc.)suffer from limited solubility of peptide segments during the journey of protein synthesis.Such hydrophobic peptides pose difficulty for subsequent purification,characterization,chemical ligation and other operations.The main factors for these problems may be that the peptide segments are prone to self-assemble into secondary structures through hydrophobic interactions,hydrogen bond or other interaction modes,thus reducing the solubility.Addition of solubilizing tags is recognized as one of the effective methods to overcome such obstacles.In this review,strategies of attaching solubilizing tags to the main chain,side chain and backbone of peptides are introduced.Membrane protein FCER1G,co-chaperone protein GroES and other proteins are selected as examples to describe the applications of the solubilizing tags.Moreover,the future of solubilizing tags strategy is discussed and prospected.

关 键 词：蛋白质化学合成 多肽 自然化学连接 片段增溶策略 疏水相互作用 

分 类 号：O629.73[理学—有机化学]